1. Field of the Invention
This invention relates to a new method for the treatment of microvascular complications associated with diabetes mellitus in mammals, particularly to those microvascular diseases associated with the vascular system of the retina, kidney, nerves and skin such as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
2. Related Disclosures
A class of pyrrolo-pyrrole compounds have now been found to be useful in the treatment of microvascular diseases associated with diabetes mellitus. The same compounds were previously known to be useful as antiinflammatories, analgesics, antipyretics and as smooth muscle relaxants. U.S. Pat. Nos. 4,232,038; 4,097,579; 4,087,539 and 4,089,969.
Diabetes mellitus is a disease resulting from a variable interaction of hereditary and environmental factors characterized by abnormal insulin secretion and a variety of metabolic and vascular manifestations reflected in a tendency toward inappropriately elevated blood glucose, thickening of capillary basal lamina, accelerated non-specific atherosclerosis, and neuropathy. Complete clinical syndrome of diabetes mellitus involves hyperglycemia, large vessel disease, microvascular disease and neuropathy.
Microangiopathies are pathological processes affecting the walls of the capillaries, the precapillary arteriols and post capillary venules. They may cause altered local blood flow, progressive reversible dilation of small veins, periodic arteriolar vessel constriction, sclerosis of the walls of arteriols, small veins and capillaries, and slowly progressing microcirculatory decompensation. The basement membranes of the attached capillaries and terminal arteriols are frequently thickening. The Merck Manual, 13th edition, 1289, (1977).
Diabetic retinopathy, one of the most pronounced complications of diabetes is a fair representative of microvascular diseases associated with diabetes. The degree of diabetic retinopathy is related to the duration. Compounds of this invention have been found useful in treating diabetic retinopathy and other microvascular complications associated with diabetes such as, for example, diabetic nephropathy or diabetic neuropathy. The effect of pyrrolo-pyrrole compounds on the microvascular diseases associated with diabetes is several-fold. Among others, the drugs prevent neovascularization, prevent leakage of macromolecules from the vessel and affect permeability of the vessel to prevent vasculary edema. Although their usefulness as anti-inflammatories, analgesics, muscle relaxants, and antipyretics, have been previously known, it is surprising to find that these compounds also result in a prevention, inhibition or regression of microvascular diseases in mammals.